Obesity is the major risk factor for the development of NIDDM in Pima Indians. Prospective studies were, therefore, initiated more than a decade ago to identify the metabolic predictors of body weight gain in this population. As of today 5 metabolic predictors of body weight gain have been identified: a low "relative" metabolic rate, a low fat to carbohydrate oxidation ratio, a low spontaneous physical activity, insulin sensitivity and a low sympathetic nervous system activity. Studies of total daily energy expenditure in five-year old children indicate that Pima Indians, like Caucasians, have very low levels of physical activity. Since physical activity in Pima children was not lower than in Caucasians, excess food intake is also likely to play a major role in the etiology of obesity in this population. After the discovery of leptin, a protein playing an important role in the regulation of food intake and energy expenditure in rodents, measurements of fasting plasma leptin concentrations were done in Pima Indians and Caucasians. Leptin concentrations were strongly related to percent body fat and were higher in those subjects with more central distribution of obesity. After adjustment for percent body fat, Pimas had similar plasma leptin concentrations to Caucasians. However, Pima Indians gaining weight had significantly lower plasma leptin concentrations than weight stable subjects. No variant of the leptin gene has been found in Pima Indians. Therefore, factors influencing leptin production or genetic variants in the promoter region of the gene may be responsible for the variability of leptin concentration among subjects. Intense investigation of the leptin receptor gene is underway in our laboratory. Based on the evidence that obesity has sizeable genetic component, a genetic search first targeting candidate genes and now extended to the entire genome has been initiated. So far, the best evidence of genes influencing body fat came from markers at chr. 11q21-q22. Also, some markers are linked to metabolic rate. These regions are being investigated for possible obesity candidate genes.